Bacterial infections and other strong stimuli may initiate an immune reaction which may cause a systemic inflammation or a systemic inflammatory response system (SIRS). A serious SIRS causes serious fever, hypotoxemia, trachypnea, tachycardia, endothelium inflammation, myocardial dysfunction, mental disorder, blood vessel collapse, and eventually a multiple organ failure syndrome (MODS) which accompanies an organ injury, e.g., an acute respiratory distress syndrome, coagulation disorder, heart failure, renal failure, shock and/or coma.
A sepsis is defined as a situation in which an infection has been confirmed or is doubted along with a systemic inflammatory response. A sever sepsis is defined as a case in which a sepsis is accompanied by an organ dysfunction (low blood pressure, hypoxia, oliguria, metabolic acidosis, thrombocytopenia, consciousness disorder). A septic shock is defined as a case in which blood pressure is not normalized even if infusion therapy is used or medicine for enhancing blood pressure is used. The sepsis may progress to a severe sepsis and finally a clinical step of a septic shock. The clinical sepsis is defined in a broad sense as a state in which the invasion by the microorganism agent is related with the clinical symbols of the infection. The clinical symbols of the sepsis are (1) Body temperature >38° C. or <36° C.; (2) Heart rate >90 times per minute; (3) Respiratory rate >20 times per minute or PaCO2<32 mmHg; (4) The number of white corpuscles >12000/cu mm, <4,000/cu mm or >10% immature (band) form; (5) organ dysfunction or high blood pressure, but the present invention is not limited to these examples.
If an infection occurs, the macrophage of the infection region is activated so as to secrete TNF-α and IL-1, thereby the amount of discharge of the plasma protein into the organs increases, the movement of phagocytes and lymphocytes to the organs increases, and the attachment of the blood platelets on the walls of the blood vessels increases. In this way, the local blood vessels are closed, and the pathogenic organisms are concentrated on the infected region. Particularly, in the sepsis, the systemic infection occurs, and the serious blood vessel closure induced by TNF-α is accompanied. Further, the systemic discharge of TNF-α causes the loss of the volume of the blood plasma due to the blood vessel enlargement and the increase of the permeability of the blood vessel, thereby causing a shock. In the septic shock, TNF-α further stimulates blood coagulation, thereby causing generation of blood clots and mass consumption of blood coagulation protein in small blood vessels. Since the blood coagulation ability of a patient is lost, important organs such as kidney, liver, heart, and lung are damaged by the dysfunction of the normal vessels. It has been reported that the mortalities of the severe sepsis and the septic shock reach 25 to 30% and 40 to 70%, respectively.
In many cases of the sepsis, the pathogenic organism is E. coli, but gram negative bacteria such as Klebsiella-Enterobacter-Serratia group and Pseudomonas may also cause such a state. Gram-positive microorganisms such as Staphylococcus, systemic viruses and Fungus may also cause the sepsis.
Urogenital vessel, gastrointestinal vessel and respiratory tract are most commonly infected regions which cause the sepsis. In addition, other sepsis-related infection regions are a cut or burn region, a pelvic infection region and a catheter infection region within a vein, etc.
The sepsis mostly frequently occurs in a hospitalized patient suffering from a basal disease or symptom sensitive to the invasion of the hematocele, or a burn, wound or surgical patient. Factors of making a person sensitive to the invasion of the hematocele are a weakened immune system, for example, an immune system of an infant or an elderly person, and a symbol or disease which increases a local sensitivity to infection, for example, a weakened circulation, diabetes, uremia and AIDS. Finally, a subject having a tendency of a weakened immune response which may occur due to the existence of various allelic genes of IL-1 gene also has a greater possibility of an outbreak of the sepsis (U.S. Pat. No. 6,251,598).
It is understood that the sepsis is generated as a result of complicated reciprocal action between bacteria causing infection and the immune, inflammation and coagulation system of the host. Both the response level of the host and the features of the bacteria causing infection significantly affect the convalescence of the sepsis. Organ failure observed in the sepsis occurs when the response to the bacteria causing the infection of the host is inappropriate, and if the response is excessively increased, the organ of the host itself may be damaged. Based on this concept, antagonists to TNF-α, IL-1β, IL-6, which are proinflammatory cytokines that perform a leading role in the inflammation response to the host, has been used in an attempt to cure the sepsis, but most of the attempts have failed, and injection of activated protein C and treatment of glucocorticoid are now being used in an attempt to cure the sepsis, but many limits are being indicated. Hence, there is a need for a new treatment for preventing or treating the sepsis and the septic shock.
SIRT1 (silent mating type information regulation 2 homolog; sirtuin 1) is known as an enzyme for regulating the function of the protein by deacetylating the lysine residue of various proteins, which depends on NAD+ (Ageing Res, Vol. 1, pages 313-326, (2002)), and is most similar to Sir2 of the yeast having (NAD+)-dependent class III histone deacetyl activity. In particularly, SIRT1 cuts the acetyl group attached on the transcription factor such as Nuclear factor-kB and p53 (Cancer Res, Vol. 64, pages 7513-7525, (2004); Cell, Vol. 107, pages 149-159, (2001); Trends Endocrinol Metab, Vol. 17, pages 186-191, (2006)). Further, SIRT1 participates in reconfiguration of chromatin related with the inhibition of gene expression, DNA damage response, life extension related with restricted diet, etc. (Chen et al., Science 310, 1641, 2005). That is, SIRT1 reconfigures chromatin through histone deacetylation as in Sir2 of the yeast, inhibits expression of gene, and induces deacetylation of various transcription factors related with cell growth, stress reaction and internal secretion regulation, etc. as well as histone protein. Further, according to a recent study, there has been a report of a technology which applies the SIRT1 to diabetes, obesity, nervous degenerative diseases or aging related diseases, etc. by increasing the deacetylation of the SIRT1.
Likewise, there is a report on pharmacological effects that the SIRT1 may be applicable to various diseases by increasing the deacetylation activity, but there is no study on pharmacological effects for preventing or treating the sepsis or septic shock. Hence, there is a need for a new treatment for preventing or treating the sepsis or septic shock.